Basic Science and Pathogenesis

Atticus H. Hainsworth; Love Onwuzuruike; Misha Ramesh; Raimondo Ascione; Colin Berry; Leslie Bridges; Diana Cash; Eddie Clutton; Carola Daniel; Betty Gao; Jeremy D. Isaacs; Simon Lillico; Jeremy Madigan; Daniel Meijles; James Nixon; Stephanie Osei; Adrian Ritchie; Monika Romanowska; Peter Tennant; Claire Warren; Joseph Westaby; C. Bruce A. Whitelaw; Steven Cr Williams

doi:10.1002/alz.085868

Basic Science and Pathogenesis

Atticus H. Hainsworth, Love Onwuzuruike, Misha Ramesh, Raimondo Ascione, Colin Berry, Leslie Bridges, Diana Cash, Eddie Clutton, Carola Daniel, Betty Gao, Jeremy D. Isaacs, Simon Lillico, Jeremy Madigan, Daniel Meijles, James Nixon, Stephanie Osei, Adrian Ritchie, Monika Romanowska, Peter Tennant, Claire WarrenJoseph Westaby, C. Bruce A. Whitelaw, Steven Cr Williams

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin-1 (ET1) causes small artery vasoconstriction and fibrosis. ET1 is implicated in microvascular disease and in VCID. There are few experimental animal models relevant to VCID [Hainsworth et al. 2017]. Pigs are higher mammals with a gyrencephalic brain and extensive subcortical white matter. METHOD: We engineered domestic pigs carrying additional copies of the ET1-encoding gene EDN1 under a Tet-ON promotor, by lentiviral injection into blastocysts. We induced transgene expression for up to 8 days using oral doxycycline in young adults. RESULT: We studied ET1-overexpressing (n = 6, 3F/3M, mean±SD age 184±61 days) and control animals (n = 5, 3F/2M, 149±41 days). Following doxycycline treatment we observed a wide range of transgene expression at mRNA level. Antibody labelling indicated a spectrum of ET1 abundance in brain and heart tissue. Heart weight was 460±106 g in ET1-overexpressing pigs and 394±25 g in controls. Brain weight: 104±14.4 g in ET1-overexpressing, 101±9.0 in controls. We will report phenotypes relevant to inflammation and blood vessel fibrosis. CONCLUSION: Adult-onset EDN1 induction in domestic pigs produces ET1 overexpression that is well-tolerated to 8 days. Reference: Hainsworth AH, et al. (2017) BMC Med.15(1):16. Translational models for vascular cognitive impairment: a review including larger species.

Original language	English
Pages (from-to)	e085868
Journal	Alzheimer's & dementia : the journal of the Alzheimer's Association
Volume	20
DOIs	https://doi.org/10.1002/alz.085868
Publication status	Published - 1 Dec 2024

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10.1002/alz.085868

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Hainsworth, A. H., Onwuzuruike, L., Ramesh, M., Ascione, R., Berry, C., Bridges, L., Cash, D., Clutton, E., Daniel, C., Gao, B., Isaacs, J. D., Lillico, S., Madigan, J., Meijles, D., Nixon, J., Osei, S., Ritchie, A., Romanowska, M., Tennant, P., ... Williams, S. C. (2024). Basic Science and Pathogenesis. Alzheimer's & dementia : the journal of the Alzheimer's Association, 20, e085868. https://doi.org/10.1002/alz.085868

@article{e87875d0e9724e43916562440e7ba5ab,

title = "Basic Science and Pathogenesis",

abstract = "BACKGROUND: Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin-1 (ET1) causes small artery vasoconstriction and fibrosis. ET1 is implicated in microvascular disease and in VCID. There are few experimental animal models relevant to VCID [Hainsworth et al. 2017]. Pigs are higher mammals with a gyrencephalic brain and extensive subcortical white matter. METHOD: We engineered domestic pigs carrying additional copies of the ET1-encoding gene EDN1 under a Tet-ON promotor, by lentiviral injection into blastocysts. We induced transgene expression for up to 8 days using oral doxycycline in young adults. RESULT: We studied ET1-overexpressing (n = 6, 3F/3M, mean±SD age 184±61 days) and control animals (n = 5, 3F/2M, 149±41 days). Following doxycycline treatment we observed a wide range of transgene expression at mRNA level. Antibody labelling indicated a spectrum of ET1 abundance in brain and heart tissue. Heart weight was 460±106 g in ET1-overexpressing pigs and 394±25 g in controls. Brain weight: 104±14.4 g in ET1-overexpressing, 101±9.0 in controls. We will report phenotypes relevant to inflammation and blood vessel fibrosis. CONCLUSION: Adult-onset EDN1 induction in domestic pigs produces ET1 overexpression that is well-tolerated to 8 days. Reference: Hainsworth AH, et al. (2017) BMC Med.15(1):16. Translational models for vascular cognitive impairment: a review including larger species.",

author = "Hainsworth, {Atticus H.} and Love Onwuzuruike and Misha Ramesh and Raimondo Ascione and Colin Berry and Leslie Bridges and Diana Cash and Eddie Clutton and Carola Daniel and Betty Gao and Isaacs, {Jeremy D.} and Simon Lillico and Jeremy Madigan and Daniel Meijles and James Nixon and Stephanie Osei and Adrian Ritchie and Monika Romanowska and Peter Tennant and Claire Warren and Joseph Westaby and Whitelaw, {C. Bruce A.} and Williams, {Steven Cr}",

note = "Publisher Copyright: {\textcopyright} 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = dec,

day = "1",

doi = "10.1002/alz.085868",

language = "English",

volume = "20",

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journal = "Alzheimer's & dementia : the journal of the Alzheimer's Association",

issn = "1552-5279",

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Hainsworth, AH, Onwuzuruike, L, Ramesh, M, Ascione, R, Berry, C, Bridges, L, Cash, D, Clutton, E, Daniel, C, Gao, B, Isaacs, JD, Lillico, S, Madigan, J, Meijles, D, Nixon, J, Osei, S, Ritchie, A, Romanowska, M, Tennant, P, Warren, C, Westaby, J, Whitelaw, CBA & Williams, SC 2024, 'Basic Science and Pathogenesis', Alzheimer's & dementia : the journal of the Alzheimer's Association, vol. 20, pp. e085868. https://doi.org/10.1002/alz.085868

TY - JOUR

T1 - Basic Science and Pathogenesis

AU - Hainsworth, Atticus H.

AU - Onwuzuruike, Love

AU - Ramesh, Misha

AU - Ascione, Raimondo

AU - Berry, Colin

AU - Bridges, Leslie

AU - Cash, Diana

AU - Clutton, Eddie

AU - Daniel, Carola

AU - Gao, Betty

AU - Isaacs, Jeremy D.

AU - Lillico, Simon

AU - Madigan, Jeremy

AU - Meijles, Daniel

AU - Nixon, James

AU - Osei, Stephanie

AU - Ritchie, Adrian

AU - Romanowska, Monika

AU - Tennant, Peter

AU - Warren, Claire

AU - Westaby, Joseph

AU - Whitelaw, C. Bruce A.

AU - Williams, Steven Cr

PY - 2024/12/1

Y1 - 2024/12/1

N2 - BACKGROUND: Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin-1 (ET1) causes small artery vasoconstriction and fibrosis. ET1 is implicated in microvascular disease and in VCID. There are few experimental animal models relevant to VCID [Hainsworth et al. 2017]. Pigs are higher mammals with a gyrencephalic brain and extensive subcortical white matter. METHOD: We engineered domestic pigs carrying additional copies of the ET1-encoding gene EDN1 under a Tet-ON promotor, by lentiviral injection into blastocysts. We induced transgene expression for up to 8 days using oral doxycycline in young adults. RESULT: We studied ET1-overexpressing (n = 6, 3F/3M, mean±SD age 184±61 days) and control animals (n = 5, 3F/2M, 149±41 days). Following doxycycline treatment we observed a wide range of transgene expression at mRNA level. Antibody labelling indicated a spectrum of ET1 abundance in brain and heart tissue. Heart weight was 460±106 g in ET1-overexpressing pigs and 394±25 g in controls. Brain weight: 104±14.4 g in ET1-overexpressing, 101±9.0 in controls. We will report phenotypes relevant to inflammation and blood vessel fibrosis. CONCLUSION: Adult-onset EDN1 induction in domestic pigs produces ET1 overexpression that is well-tolerated to 8 days. Reference: Hainsworth AH, et al. (2017) BMC Med.15(1):16. Translational models for vascular cognitive impairment: a review including larger species.

AB - BACKGROUND: Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin-1 (ET1) causes small artery vasoconstriction and fibrosis. ET1 is implicated in microvascular disease and in VCID. There are few experimental animal models relevant to VCID [Hainsworth et al. 2017]. Pigs are higher mammals with a gyrencephalic brain and extensive subcortical white matter. METHOD: We engineered domestic pigs carrying additional copies of the ET1-encoding gene EDN1 under a Tet-ON promotor, by lentiviral injection into blastocysts. We induced transgene expression for up to 8 days using oral doxycycline in young adults. RESULT: We studied ET1-overexpressing (n = 6, 3F/3M, mean±SD age 184±61 days) and control animals (n = 5, 3F/2M, 149±41 days). Following doxycycline treatment we observed a wide range of transgene expression at mRNA level. Antibody labelling indicated a spectrum of ET1 abundance in brain and heart tissue. Heart weight was 460±106 g in ET1-overexpressing pigs and 394±25 g in controls. Brain weight: 104±14.4 g in ET1-overexpressing, 101±9.0 in controls. We will report phenotypes relevant to inflammation and blood vessel fibrosis. CONCLUSION: Adult-onset EDN1 induction in domestic pigs produces ET1 overexpression that is well-tolerated to 8 days. Reference: Hainsworth AH, et al. (2017) BMC Med.15(1):16. Translational models for vascular cognitive impairment: a review including larger species.

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U2 - 10.1002/alz.085868

DO - 10.1002/alz.085868

M3 - Article

C2 - 39751408

AN - SCOPUS:85214479586

SN - 1552-5279

VL - 20

SP - e085868

JO - Alzheimer's & dementia : the journal of the Alzheimer's Association

JF - Alzheimer's & dementia : the journal of the Alzheimer's Association

ER -

Basic Science and Pathogenesis

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